US4424370A - Cyclic acetals of N-acylglutamic acid-γ-semialdehydes, process for their production and use - Google Patents

Cyclic acetals of N-acylglutamic acid-γ-semialdehydes, process for their production and use Download PDF

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Publication number
US4424370A
US4424370A US06/320,129 US32012981A US4424370A US 4424370 A US4424370 A US 4424370A US 32012981 A US32012981 A US 32012981A US 4424370 A US4424370 A US 4424370A
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grams
acid
reaction
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compound
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Axel Kleemann
Marc Samson
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Evonik Operations GmbH
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Degussa GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

  • the present invention is directed to a cyclic acetal of N-acylglutamic acid- ⁇ -semialdehyde of the formula ##STR3## in which A is an unsubstituted alkylene group having 2 to 3 carbon atoms or such an alkylene group substituted by 1 to 2 methyl groups and R is a methyl, methoxy, phenyl, or benzyloxy group and to a method of producing a compound of formula (I) by reaction of a compound of the general formula ##STR4## in which A is as defined above with hydrogen cyanide or a cyanide ion supplying compound, ammonia or an ammonium ion supplying compound and carbon dioxide or a carbonate ion supplying compound, a basic hydrolysis of the reaction mixture obtained, and acetylation of the hydrolysis mixture.
  • a further object of the invention therefore is the use of the products to produce the corresponding N-acyltryptophane.
  • L-tryptophane is an essential aminoacid which frequently represents the limiting aminoacid in fodders and mixed fodders. Since L-tryptophane can be obtained by the enzymatic splitting of D,L-N-acyl-tryptophanes, their synthesis has great significance.
  • the cyclic acetals of N-acylglutamic acid- ⁇ -semialdehyde of the general formula (I) can be produced by a process comprising (a) reacting a compound of the general formula ##STR5## in which A is as defined above in a aqueous or aqueous-alcoholic solution with hydrogen cyanide or a cyanide ion supplying compound, ammonia or an ammonium ion supplying compound and carbon dioxide or a carbonate ion supplying compound and (b) hydrolyzing the reaction mixture obtained in step (a) under basic conditions and (c) reacting the hydrolysis mixture obtained in step (b) with a suitable acylating compound.
  • Examples of the compounds employed of general formula (II) are 2-(2'-formylethyl)-1,3-dioxolane, 2-(2'-formylethyl)-1,3-dioxane or 2-(2'-formylethyl)-5,5-dimethyl-1,3-dioxane.
  • the compounds of general formula (II) are reacted in a first reaction step which is known in itself for the formation of hydantoins from aldehydes with hydrogen cyanide or a cyanide ion supplying compound, such as sodium cyanide or potassium cyanide with ammonia or an ammonium ion supplying compound, such as ammonium hydroxide or ammonium chloride, and with carbon dioxide or a carbonate ion supplying compound, such as sodium or potassium carbonate, sodium or potassium bicarbonate, or sodium or potassium carbamate.
  • cyanide and ammonium ions such as ammonium-cyanide, or which simultaneously supply ammonium and carbonate ions, such as ammonium carbonate, or ammonium carbamate.
  • the reaction in the first reaction step takes place in water or in a mixture of water and methanol or ethanol. It can be undertaken in a wide temperature range. Preferably there is employed a temperature between 30° and 90° C., because in this range a satisfactory reaction speed is attained and the perhaps necessary superatmospheric pressure does not create an industrial obstacle.
  • the amounts of the individual reactants can be varied within a wide range.
  • the compounds of general formula (II) can be reacted simultaneously with all three other reactants. However, it is likewise also possible to first react them with the cyanide component and subsequently react simultaneously with the two other components, or first to react them only with the cyanide component, then react only with the ammonium component and only after that react with the carbon dioxide of carbonate component.
  • the reaction mixture after carrying out the first reaction step contains besides the expected hydantoin of the general formula ##STR7## also a more or less large portion of the ⁇ -N-carbamoyl-carboxylic acid amide of the general formula ##STR8## wherein in formula (IV) and (V) A is again as defined above.
  • step (a) the mixture of compounds of general formula (IV) and (V) obtained in step (a) are reacted under basic hydrolysis conditions for forming the ⁇ -aminoacids from the corresponding substituted hydantoins in a manner known of itself.
  • alkali or alkaline earth metal hydroxides or alkaline metal carbonates in aqueous medium for example, there can be used with good success NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Ca(OH) 2 or Ba(OH) 2 .
  • the reaction temperature can be varied in a wide range between 20° C. and 200° C. Preferred are temperatures between 100° C. and 150° C. since in this range satisfactory reaction speeds can be attained.
  • Especially preferred saponification conditions are temperatures between 130° C. and 150° C., reaction times of 0.5 to 1 hour and a mole ratio of substrate to base of 1:2.2.
  • the hydrolysis mixture after carrying out process step (b) contains an aqueous solution of the corresponding salt of glutamic acid- ⁇ -semialdehyde-acetal.
  • This hydrolysis mixture can be employed directly for process step (c). However, it can be suitable before carrying out the third reaction step to remove ammonia which is dissolved in the crude hydrolysis mixture by heating at normal pressure or in a vacuum.
  • reaction step (c) the aqueous solution of glutamic acid- ⁇ -semialdehyde-acetal obtained in step (b) is reacted with suitable acylating agents.
  • suitable acylating agents employed in aqueous medium are acetyl chloride, acetic anhydride, methyl chloroformate, benzoyl chloride, or benzyloxycarbonyl chloride.
  • acetyl bromide benzoyl bromide
  • benzyloxycarbonyl bromide benzyloxycarbonyl bromide.
  • Reaction step (c) is suitably carried out at a pH above 7.
  • the reaction temperature can be varied within wide limits. Suitable are temperatures between 0° and 80° C., preferably between 0° and 25° C.
  • the acylating reagents can be employed in excess. However, for economical reasons it is more advantageous to only employ the amount equivalent to the amount of compound of general formula (II) in reaction step (a).
  • the acylating agents can be added all at once to the mixture obtained from reaction step (b). However, it is more advantageous to slowly feed the acylating reagents into the mixture obtained from reaction step (b). In both cases, a reaction time of about 1 hour totally is generally sufficient.
  • N-acyl-tryptophane from the N-acylglutamic acid- ⁇ -semialdehyde-acetals they are reacted at a pH between 0.1 and 4, preferably between 1 and 3, with phenylhydrazine.
  • the required pH can be established by an inorganic acid such as sulfuric acid or phosphoric acid, by an organic acid such as oxalic acid, formic acid, acetic acid, benzenesulfonic acid or p-toluenesulfonic acid or by a strongly acid ion exchanger, e.g. a sulfonated styrene-divinyl benzene resin.
  • a strongly acid ion exchanger e.g. a sulfonated styrene-divinyl benzene resin.
  • hydrochloric acid Preferably there is used hydrochloric acid.
  • the reaction temperature can be varied within wide limits. Suitable are temperatures between 60° and 150° C., preferably between 70° and 120° C.
  • the phenylhydrazine can be employed in excess. However, for economical reasons it is more advantageous to only use the amount which is equivalent to the N-acylglutamic acid- ⁇ -semialdehyde-acetal employed.
  • the phenylhydrazine can be mixed with the N-acylglutamic acid- ⁇ -semialdehyde-acetal and the necessary amount of acid and be heated to the desired reaction temperature.
  • the solution of the N-acyltryptophane obtained can be concentrated and the residue recrystallized.
  • the N-acyltryptophane can also be crystallized by cooling the reaction mixture, and isolated by filtration.
  • the process can comprise, consist essentially of, or consist of the stated steps with the recited materials.
  • reaction solution was briefly concentrated in vacuum and treated within 30 minutes at 0° to 5° C. with 48.9 ml of a 50% solution of benzyl chloroformate in toluene. After further stirring for 30 minutes the solution was adjusted to pH 2 with concentrated hydrochloric acid, whereby a colorless oil separated, which upon being allowed to stand, slowly crystallized. The crystals were filtered off, then washed with water and dried in a vacuum. By recrystallization from benzene there were obtained 24.2 grams of N-benzyloxycarbonylglutamic acid- ⁇ -semialdehyde-ethylene-acetal.
  • Example 12 In a manner analogous to Example 12 8 grams of N-benzoylglutamic acid- ⁇ -semialdehyde-2,2-dimethylpropylene-1,3-acetal from Example 7 and 3.6 grams of phenylhydrazine hydrochloride were converted into 5.4 grams of N-benzoyl-D,L-tryptophane (70% of theory).
  • German priority application P 3043252.1-42 is hereby incorporated by reference.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
US06/320,129 1980-11-15 1981-11-10 Cyclic acetals of N-acylglutamic acid-γ-semialdehydes, process for their production and use Expired - Fee Related US4424370A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3043252 1980-11-15
DE3043252A DE3043252C2 (de) 1980-11-15 1980-11-15 Cyclische Acetale von N-Acylglutaminsäure -γ- semialdehyden, Verfahren zu deren Herstellung und ihre Verwendung

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US (1) US4424370A (de)
EP (1) EP0052200B1 (de)
JP (1) JPS57114586A (de)
DE (2) DE3043252C2 (de)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501909A (en) * 1982-08-12 1985-02-26 Sagami Chemical Research Center Aminopolyol derivatives
US4506085A (en) * 1983-03-09 1985-03-19 Sanraku-Ocean Co., Ltd. β-Aminoacid derivatives and process for production thereof
US4749800A (en) * 1987-03-09 1988-06-07 National Starch And Chemical Corporation Polysaccharide esters containing acetal and aldehyde groups
US6133002A (en) * 1997-09-25 2000-10-17 Dsm N.V. Process for preparing optically active 2-amino-ω-oxoalkanoic acid derivatives
US6166227A (en) * 1998-07-15 2000-12-26 Bristol-Myers Squibb Co. Preparation of (S)-2-amino-6, 6-dimethoxyhexanoic acid methyl ester via novel dioxolanes
CN104797592A (zh) * 2012-10-09 2015-07-22 诺华股份有限公司 基于缩醛的生产大环缩酚酸肽类的方法和新的中间体
US9127044B2 (en) 2007-08-17 2015-09-08 Novartis Ag Cyclic depsipeptides
US9662249B2 (en) 2002-09-12 2017-05-30 Edgewell Personal Care Brands, Llc. Ergonomic tampon applicator
US10105267B2 (en) 2003-05-02 2018-10-23 Edgewell Personal Care Brands, LLC> Tampon assembly having a shaped pledget
US10575994B2 (en) 2006-06-12 2020-03-03 Edgewell Personal Care Brands, Llc Tampon assembly providing proper bodily placement of pledget

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1007113C2 (nl) * 1997-09-25 1999-03-26 Dsm Nv Werkwijze voor de bereiding van optisch actieve 2-amino-omega- oxoalkaanzuurderivaten.
US8680054B2 (en) 2011-04-20 2014-03-25 Novartis Ag Suspension type topical formulations comprising cyclic depsipeptide
US8614289B2 (en) 2011-04-20 2013-12-24 Novartis Ag Processes for the manufacture of macrocyclic depsipeptides and new intermediates
US9067978B2 (en) 2012-10-09 2015-06-30 Novartis Ag Solution phase processes for the manufacture of macrocyclic depsipeptides and new intermediates

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1816703U (de) 1960-06-14 1960-08-18 Bernhard Dipl Ing Loda Hemd oder bluse mit vorderer knopfreihe.
DE2011917A1 (en) 1970-03-13 1971-09-30 Badische Anilin- & Soda-Fabrik Ag, 6700 Ludwigshafen Serine deriv prepn from isocyanoacetatesand carbonyl cpds
US3787471A (en) 1969-02-13 1974-01-22 Dow Chemical Co Dithio-and thiono-carbamate mineral value collectors
US4376864A (en) 1980-11-15 1983-03-15 Degussa Ag Cyclic acetals of glutamic acid-γ-semialdehyde, process for their production and use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2557920A (en) * 1946-11-07 1951-06-19 Dow Chemical Co Method for production of amino acids
ZA783356B (en) * 1977-07-21 1979-06-27 Merrell Toraude & Co A-halomethyl amino acid derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1816703U (de) 1960-06-14 1960-08-18 Bernhard Dipl Ing Loda Hemd oder bluse mit vorderer knopfreihe.
US3787471A (en) 1969-02-13 1974-01-22 Dow Chemical Co Dithio-and thiono-carbamate mineral value collectors
DE2011917A1 (en) 1970-03-13 1971-09-30 Badische Anilin- & Soda-Fabrik Ag, 6700 Ludwigshafen Serine deriv prepn from isocyanoacetatesand carbonyl cpds
US4376864A (en) 1980-11-15 1983-03-15 Degussa Ag Cyclic acetals of glutamic acid-γ-semialdehyde, process for their production and use

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501909A (en) * 1982-08-12 1985-02-26 Sagami Chemical Research Center Aminopolyol derivatives
US4506085A (en) * 1983-03-09 1985-03-19 Sanraku-Ocean Co., Ltd. β-Aminoacid derivatives and process for production thereof
US4749800A (en) * 1987-03-09 1988-06-07 National Starch And Chemical Corporation Polysaccharide esters containing acetal and aldehyde groups
US6291701B1 (en) 1997-09-25 2001-09-18 Dsm N.V. Process for preparing optically active 2-amino-ω-oxoalkanoic acid derivatives
US6133002A (en) * 1997-09-25 2000-10-17 Dsm N.V. Process for preparing optically active 2-amino-ω-oxoalkanoic acid derivatives
US6720169B1 (en) 1997-09-25 2004-04-13 Dsm N.V. Process for preparing optically active 2-amino-w-oxoalkanoic acid
US6222052B1 (en) 1997-09-25 2001-04-24 Dsm N.V. Process for preparing optically active 2-amino-ω-oxoalkanoic acid derivatives
US6329542B1 (en) 1998-07-15 2001-12-11 Bristol-Myers Squibb Co. Preparation of (S)-2-amino-6,6-dimethoxyhexanoic acid methyl ester via novel dioxolanes
US6248882B1 (en) 1998-07-15 2001-06-19 Bristol-Myers Squibb Co. Preparation of (s)-2-amino-6,6-dimethoxyhexanoic acid methyl ester via novel dioxolanes
US6166227A (en) * 1998-07-15 2000-12-26 Bristol-Myers Squibb Co. Preparation of (S)-2-amino-6, 6-dimethoxyhexanoic acid methyl ester via novel dioxolanes
US9662249B2 (en) 2002-09-12 2017-05-30 Edgewell Personal Care Brands, Llc. Ergonomic tampon applicator
US10105267B2 (en) 2003-05-02 2018-10-23 Edgewell Personal Care Brands, LLC> Tampon assembly having a shaped pledget
US10105266B2 (en) 2003-05-02 2018-10-23 Edgewell Personal Care Brands, Llc. Tampon assembly having a shaped pledget
US10383776B2 (en) 2003-05-02 2019-08-20 Edgewell Personal Care Brands, Llc Tampon assembly having a shaped pledget
US10575994B2 (en) 2006-06-12 2020-03-03 Edgewell Personal Care Brands, Llc Tampon assembly providing proper bodily placement of pledget
US9127044B2 (en) 2007-08-17 2015-09-08 Novartis Ag Cyclic depsipeptides
CN104797592A (zh) * 2012-10-09 2015-07-22 诺华股份有限公司 基于缩醛的生产大环缩酚酸肽类的方法和新的中间体

Also Published As

Publication number Publication date
EP0052200A1 (de) 1982-05-26
DE3163996D1 (en) 1984-07-12
EP0052200B1 (de) 1984-06-06
DE3043252C2 (de) 1982-12-02
JPS57114586A (en) 1982-07-16
DE3043252A1 (de) 1982-06-09

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